Vagus nerve stimulation (VNS) is effective for the treatment of refractory partial epilepsy, and has been approved for human use in the European Community. However, little is known about neural mechanisms that mediate its anticonvulsant effect. In humans, left VNS is administered intermittently, but optimal stimulation parameters are not known. Since partial onset seizures originate in the forebrain, it is likely that VNS utilizes mechanisms that project from the brainstem vagal afferent system. Data on regional brain fos expression suggest that VNS affects several brain structures that are highly epileptogenic or regulate seizures. Specific aim 1 will study temporal aspects of VNS and will determine if the anticonvulsant effect of VNS persists beyond stimulus duration, if its efficacy is dependent on total VNS duration, and whether intermittent VNS is more or less effective than constant stimulation. The left vagus nerve will be stimulated (l mA, 30 Hz, 500 mu sec pulses) in Sprague-Dawley (S- D) rats with constant (0,1 or 60 min) or intermittent (30 sec on, 5 min off, 60 min total) VNS. After VNS seizures will be induced by either pentylenetetrazol or maximal electroshock. The mean seizure latency, duration and severity will be measured in each groups, and compared to controls (0 min) to determine if VNS pretreatment is effective, and if there are differences in efficacy due to total stimulation duration or constancy of stimulation. Aim l will also determine the time course of VNS effect in S-D rats by measuring the effects of seizure provocation by PTZ and MES at increasing intervals after the end of VNS. Aim 2 will determine if there are differences in VNS efficacy that are dependent on whether seizures are initiated in the forebrain or brainstem. The effect of VNS pretreatment and abortive therapy will be studied in l) a model of forebrain onset seizures (electrically kindled seizures of the amygdala in the S-D rat) and 2) a model of brainstem onset seizures (audiogenic seizures in the genetically epilepsy-prone rat, GEPR-9). Aim 3 will determine if there are VNS induced alterations in regional glucose metabolism In brains of S-D rats. This study will compare (14C] 2- deoxyglucose autoradiographs from unstimulated S-D animals to those that have received either constant or intermittent left VNS for 45 min. Areas that will be examined have been previously identified to be activated by VNS in fos studies. Structures that are highly epileptogenic or regulate seizures in other models will also be examined. Aim 4 will determine if VNS has an antiepileptogenic effect, i.e., prevents the progressive worsening of seizures that occurs as a result of repetitive seizure provocations. VNS will be administered prior to each seizure provocation in l) the electrical amygdala kindling model in the S-D rat and 2) audiogenic seizure repetition in the GEPR-9, and will be compared to animals receiving no pretreatment. Aim 5 will determine if VNS reduces levels of glutamate or aspartate, or increases GABA, norepinephrine or serotonin levels in VNS-affected structures identified by previous studies or structures that are highly epileptogenic or regulate seizures, using in vivo microdialysis probe and measurement of neurotransmitter levels before, during and after VNS. The results from this study will provide important information to improve VNS therapy for intractable epilepsy and will identify neuronal mechanisms that may lead to other novel therapies for epilepsy and other neurologic disorders.